67 kDa laminin receptor: structure, function and role in cancer and infection (original) (raw)
Related papers
Journal of Biological Chemistry, 1997
The interactions between tumor cells and laminin or other components of the extracellular matrix have been shown to play an important role in tumor invasion and metastasis. However, the role of the monomeric 67-kDa laminin receptor (67LR) remains unclear. We analyzed the regulation of 67LR expression under different culture conditions with respect to the expression of other well characterized laminin receptors. In A431 cells treated with laminin for different time periods, the regulation of 67LR expression correlated with expression of the ␣6 integrin subunit but not with the expression of other laminin receptors. Moreover, cytokine treatment resulted in down-modulated expression of the ␣6 integrin subunit and the 67LR. Co-regulation of the expression of the two receptors was further suggested by the observation that specific down-modulation of the ␣6chain by antisense oligonucleotides was accompanied by a proportional decrease in the cell surface expression of 67LR. Biochemical analyses indicated co-immunoprecipitation of 67LR and the ␣6 subunit with an anti-␣6 but not an anti-1 monoclonal antibody. Co-regulation of 67LR and ␣6 subunit expression, together with the physical association between the two receptors, supports the hypothesis that 67LR is an auxiliary molecule involved in regulating or stabilizing the interaction of laminin with the ␣64 integrin.
The 67kDa laminin receptor increases tumor aggressiveness by remodeling laminin-1
The association between expression of the 67 kDa laminin receptor (67LR) and tumor aggressiveness has been convincingly demonstrated although the exact function of this molecule in the metastatic process has remained unclear. In this study, we tested whether the laminin-1, upon interaction with 67LR, promotes tumor cell aggressiveness; the investigation was based on: (i) the previous demonstration that soluble 67LR, as well as a 20-amino-acid peptide corresponding to the 67LR laminin binding site, changes the conformation of laminin upon interaction with this adhesion molecule and (ii) the known relevance of microenvironment remodeling by the tumor, leading to structural modification of extracellular matrix components in tumor progression. MDAMB231 breast carcinoma cells plated on peptide G-treated laminin-1 exhibited a polygonal array of actin filament bundles compared with cells seeded on native laminin-1 which presented the actin bundles organized as multiple cables parallel to margins. Furthermore, in cells seeded on peptide G-treated laminin-1, 67LR was distinct from the a6 integrin subunit in filopodia protrusions in addition to colocalizing with this integrin in focal adhesion plaques as it occurs when cells are plated on native laminin-1. In addition to differences in tumor cell adhesion and migration found in cells exposed to peptide G-treated vs native laminin-1, breast carcinoma cells seeded on modified laminin-1 showed a 6-fold increase in invasion capability compared with cells seeded on unmodified laminin-1. Alterations in actin organization as well as adhesion, migration and especially invasion observed in MDAMB231 cells in the presence of peptide G-treated laminin-1 were even found in MDAMB231 cells that, after selection for 67LR high expression, were seeded on native laminin-1. As the 67LR shedding is proportional to its expression level, these findings indicate a role for 67LR in changing laminin structure.
Journal of Biological Chemistry, 1997
The interactions between tumor cells and laminin or other components of the extracellular matrix have been shown to play an important role in tumor invasion and metastasis. However, the role of the monomeric 67-kDa laminin receptor (67LR) remains unclear. We analyzed the regulation of 67LR expression under different culture conditions with respect to the expression of other well characterized laminin receptors. In A431 cells treated with laminin for different time periods, the regulation of 67LR expression correlated with expression of the ␣6 integrin subunit but not with the expression of other laminin receptors. Moreover, cytokine treatment resulted in down-modulated expression of the ␣6 integrin subunit and the 67LR. Co-regulation of the expression of the two receptors was further suggested by the observation that specific down-modulation of the ␣6chain by antisense oligonucleotides was accompanied by a proportional decrease in the cell surface expression of 67LR. Biochemical analyses indicated co-immunoprecipitation of 67LR and the ␣6 subunit with an anti-␣6 but not an anti-1 monoclonal antibody. Co-regulation of 67LR and ␣6 subunit expression, together with the physical association between the two receptors, supports the hypothesis that 67LR is an auxiliary molecule involved in regulating or stabilizing the interaction of laminin with the ␣64 integrin. 2 S. Butò, E. Tagliabue, E. Ardini, A. Magnifica, V. Castronovo, M. I. Colnaghi, M. Sobel, and S. Ménard, manuscript in preparation.
Expression of 32/67-kDa laminin receptor in laminin adhesion-selected human colon cancer cell lines
British Journal of Cancer, 1998
Laminin promotes the malignant phenotype, and the expression of certain laminin receptors is increased in malignancy. Previously, we demonstrated that a laminin-adhesive subolone of a human colon cancer cell line showed increased tumorigenicity in nude mice and increased affinity of the P, integrin for laminin relative to the laminin-non-adhesive subolone. The total amount of either 1 integrin protein or mRNA did not increase. As levels of the 32/67-kDa laminin receptor (67LR) correlate with malignancy, we examined 67LR expression in the laminin adhesion-selected human colon cancer cells. The laminin-adhesive subolone, which was more tumorigenic in both heterotopic and orthotopic locations than in a laminin-non-adhesive subolone, showed cell-surface membrane staining of 67LR, whereas the laminin-non-adhesive subolone showed cytoplasmic staining of 67LR. No difference in either the amount of 67LR mRNA or the amount of protein was observed in the parental cells than in the laminin-adhesive and non-adhesive subolones. When assayed on a laminin affinity column, more 67LR molecules bound to the column with cell extracts from the laminin-adhesive subolone than was observed with the nonadhesive subclone. These findings suggest that the increased tumorigenicity of laminin adhesion-selected tumour cells might be due to an alteration in the distribution and/or adhesiveness of multiple receptors including 67LR and P1 integrin.
Journal of Biological Chemistry, 1996
We investigated the effect of peptide G, a synthetic peptide derived from the sequence of the 37-kDa laminin receptor precursor, on the interaction of laminin in two tumor cell lines one of which produces laminin and one of which does not. Addition of peptide G to the culture medium induced a significant increase in the amount of endogenous laminin detectable on the cell membrane of both cell lines. Moreover, pretreatment of exogenous laminin with peptide G dramatically increased laminin binding on both cell lines. Kinetics analysis of membrane-bound labeled laminin revealed a 3-fold decrease in the k d of peptide G-treated laminin compared with untreated or unrelated or scrambled peptide-treated laminin. Moreover, the affinity constant of peptide G-treated laminin increased 2-fold, with a doubling of the number of laminin binding sites, as determined by Scatchard analysis. Expression of the VLA6 integrin receptor on the cell membrane increased after incubation with peptide G-treated laminin. However, the lower binding inhibition of peptide G-treated laminin after anti-VLA6 antibody or cation chelation treatment indicates that membrane molecules in addition to integrin receptors are involved in the recognition of peptide G-modified laminin. These "new" laminin-binding proteins also mediated cell adhesion to laminin, the first step in tumor invasion. Together, the data suggest that peptide G increases and stabilizes laminin binding on tumor cells, involving surface receptors that normally do not take part in this interaction. This might explain the abundant clinical and experimental data suggesting a key role for the 67-kDa laminin receptor in the interaction between cancer cells and the basement membrane glycoprotein laminin during tumor invasion and metastasis.
A 33-kDa Polypeptide with Homology to the Laminin Receptor: Component of Translation Machinery
Proceedings of The National Academy of Sciences, 1992
A 33-kDa polypeptide (termed p40), which shares an antigenic determinant with a laminin receptor and is under translational control, is believed to serve as a precursor to the receptor and to be related to the neoplastic state. The present study of subcellular localization of this protein shows it to be a cytoplasmic component not associated with the plasma membrane. Most of the cellular p40 was found to be associated with polyribosomes as well as with 40S to 60S cytoplasmic particles. Conditions that lead to polysome disruption also caused release of the polysomal form of p40 as smaller particles, and polysome reconstitution was accompanied by uptake of p40 into these structures. Because of the large abundance of this protein in the cells (six to eight copies per ribosome), it is unlikely that it represents a factor that associates with the 40S preinitiation complex. The p40-containing particles appear to represent a newly discovered structure involved in the process of polysome formation.
Oncotarget, 2015
The 67 kDa laminin receptor (67LR) is a non-integrin receptor for laminin (LM) that derives from a 37 kDa precursor (37LRP). 67LR expression is increased in neoplastic cells and correlates with an enhanced invasive and metastatic potential.We used structure-based virtual screening (SB-VS) to search for 67LR inhibitory small molecules, by focusing on a 37LRP sequence, the peptide G, able to specifically bind LM. Forty-six compounds were identified and tested on HEK-293 cells transfected with 37LRP/67LR (LR-293 cells). One compound, NSC47924, selectively inhibited LR-293 cell adhesion to LM with IC50 and Ki values of 19.35 and 2.45 μmol/L.NSC47924 engaged residues W176 and L173 of peptide G, critical for specific LM binding. Indeed, NSC47924 inhibited in vitro binding of recombinant 37LRP to both LM and its YIGSR fragment. NSC47924 also impaired LR-293 cell migration to LM and cell invasion.A subsequent hierarchical similarity search with NSC47924 led to the identification of addition...
European Journal of Biochemistry, 1989
The laminin proteolytic fragments 1 (derived from the intersection of the short arms of the cruciform laminin molecule) and 8 (derived from the laminin long arm) bind to distinct receptors on HT-1080 human fibrosarcoma cells; both fragments are shown here to inhibit the high-affinity binding of laminin to these cells. Inhibition of binding between fragment 8 and laminin was competitive, whereas that between fragment 1 and laminin was noncompetitive. This indicates that laminin and fragment 8 most probably share the same cellular receptors, whereas laminin and fragment 1 bind to distinct receptors, inhibition being due to steric hindrance. Surprisingly, fragment 1 -4 (corresponding to the complete short arms of laminin) neither bound to HT-1080 cells nor inhibited the binding of laminin or fragment 1. After treatment of fragment 1-4 with pepsin, however, the smaller subfragment 1 was liberated, which could then bind to the cells, and so was shown to block the binding of laminin and fragment 1. We conclude that native laminin bound to HT-1080 cells via the fragment-%binding site near the end of its long arm. Although these cells also have distinct receptors for the short arm fragment 1, this receptorbinding site was not used as it appeared to be latent within the native laminin molecule.
Journal of Biological Chemistry
Laminin-and elastin-binding proteins were isolated by ligand affinity chromatography from plasma membranes of fetal bovine auricular chondroblasts and human A2068 melanoma cells. From both cell types, a 67-kDa protein was identified which bound to either elastin or laminin affinity resins. Structural and functional similarities between the elastin and lamininbinding proteins were suggested by 1) cross-reactivity between antibodies directed against the two proteins; 2) elution of the laminin receptor from laminin columns with soluble elastin peptides; and 3) modulation of substrate binding by galactoside sugars. In addition, extraction properties indicate that both receptors are peripheral membrane proteins whose association with the cell surface is mediated by their lectin properties. Mapping of the binding site on laminin suggests that the 67-kDa chondroblast receptor interacts with a hydrophobic elastin-like sequence in domain V of the B1 chain, and chemotaxis studies indicate that cell migration to elastin peptides and laminin involves the same receptor.
Oral Oncology, 2007
Adenoid cystic carcinoma is a malignant salivary gland neoplasm with recurrence and metastasis. We studied the expression of a malignancy-related non-integrin laminin receptor, the 67LR, in this neoplasm. Immunohistochemistry showed 67LR in adenoid cystic carcinoma. This receptor binds a sequence of laminin b1 chain, the YIGSR peptide. We studied the effect of 67LR and YIGSR in cells (CAC2) from adenoid cystic carcinoma. Three-dimensional cultures of cells embedded into either laminin-111 gel (controls) or YIGSR-enriched laminin-111 (treated) were prepared and studied by light microscopy. CAC2 cells treated with YIGSR appeared fibroblast-like, while control cells were epithelioid. Blockage of 67LR by antibody abolished YIGSR effect in three-dimensional cultures. We analysed the relevance of 67LR and YIGSR on b-catenin expression in CAC2 cells. Immunofluorescence and immunoblot showed that YIGSR decreased b-catenin, while blockage of 67LR restored the presence of this molecule. The 67LR and YIGSR induced fibroblast-like morphology in CAC2 cells, with disruption of cell-cell contacts and decrease of b-catenin. These features resemble epithelial-mesenchymal transition (EMT). EMT also increases cell migration. In monolayer assays YIGSR increased migration of CAC2 cells. We conclude that 67LR and YIGSR are involved in epithelial-mesenchymal transition, modulation of b-catenin expression, and migratory activity of CAC2 cells.